In general, optical isomers, which are isomers having relation of a mirror image and a real image, are identical in physical and chemical properties except a rotatory power. Therefore, it is difficult to obtain only one isomer at high optical purity.
Accordingly, a cheap racemic body which is an equivalent mixture of optical isomers is typically used for a material or the like where emphasis is placed on chemical and physical properties. Meanwhile, an optically active substance composed only of one isomer has been used in many cases in the fields of drugs, biochemistry-related industry, and the like. This is because of one of the important properties of an optical isomer: the optical isomers may show different interactions when they affect an optically active substance.
For this reason, in the real state, in particular in case of drugs, the development of a drug composed of a single optically active substance intended for reducing a dosage for preventing damage from medicines and for suppressing side effects has been desired in consideration of the possibility that optical isomers may show different drug effects, different side effects, and the like between each of the optical isomers to living body (which is an optically active substance composed of an optically active amino acid, an optically active sugar, and the like).
As described above, to obtain an optically active substance having high optical purity is more difficult and more expensive than the production of a racemic body. Various methods have been attempted to solve the problem.
The methods are roughly classified into: a method involving optically resolving a racemic body to obtain one optically active substance; a method involving directly producing an optically active substance from a prochiral compound; and a method called a chiral pool method involving producing a target optically active substance by means of a cheap optically active substance as a starting material. Each method has its merits and demerits, and, at present, it has been difficult to satisfy all the items concerning productivity by means of a single method.
Examples of the method involving optically resolving a racemic body to obtain one optically active substance include crystallization by means of a diastereomer salt, a bio method such as asymmetric utilization, and a method of producing an optically active substance according to liquid chromatography.
A method of producing an optically active substance according to liquid chromatography recently developed has a potential to contribute to the quick establishment of a production approach including the setting of production conditions once analysis conditions are set because the method of producing an optically active substance is applicable to a wide variety of optical isomer compounds and because a large number of techniques for analyzing the optical purity of an optical isomer have involved the use of a separating column for an optical isomer at present (see, for example, Shigeo Makino, PHARM TECH JAPAN, 12, 43 (1996), Shigeo Makino, Tetsuji Yanami, Bunri Gijutsu, 26, 15 (1996), Y. Okamoto, Angew. Chem. Int. Ed., 37, 1020 (1998), and Y. Okamoto, Synlett, 1998, 344).
Several papers (see, for example, J. Chromatogr., A, 832, 55 (1999)) have been reported heretofore for a technique to producing Ethyl (3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl]-3,5-dihydroxy-6-heptenoate. In addition, patents have been filed heretofore for the production technique (see, for example, WO 02/30903 and WO 95/23125). However, the development a packing material for separating an optical isomer and a production approach that can show improved productivity has been strongly desired.
The present invention provides a method of producing Ethyl (3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl]-3,5-dihydroxy-6-heptenoate with higher productivity than that of a conventional method.